Experimental Drug Improves Memory in Mice Models of Multiple Sclerosis

Investigators have reported the effective use of a form of magnetic resonance imaging (MRI) to identify what appears to be a key biochemical marker for cognitive impairment in the brains of individuals with multiple sclerosis (MS). In follow-up research on mice with a rodent form of MS, researchers were able to use an experimental agent to modify that same marker, which resulted in greatly improving learning and memory.

Half of people with MS experience learning and memory difficulties—for which there is no approved treatment—along with movement abnormalities that characterize the debilitating autoimmune disorder. “We have a potentially novel treatment for cognitive impairment in MS, a devastating condition on the rise that affects at least 400,000 people in the United States,” said study leader Adam I. Kaplin, MD, PhD, an assistant professor of psychiatry and behavioral sciences and neurology at the Johns Hopkins University School of Medicine (Baltimore, MD, USA).

Dr. Kaplin warned that the treatment has so far been used only in mouse models of MS and is years away from clinical trials in people. Nevertheless, he noted, the research, published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) published online in November 2012, has the potential to speed development of new drugs to treat cognitive impairment not only in MS patients, but also in patients with Alzheimer’s disease and other neurologic disorders.

MRI scan of brain lesions can frequently reveal how much damage the disease is doing to the brain, and those findings often correlate with physical disability. However, until now, according to Dr. Kaplin, there has been no way to link these image findings with cognitive impairment. For the study, Dr. Kaplin and his colleagues employed magnetic resonance spectroscopy (MRS), which uses conventional MRI scanners but adds tests to identify and compare various brain chemicals found on the images. The Johns Hopkins investigators performed the tests on nine occasions on the brains of subjects with MS, focusing on the hippocampus, looking at levels of various brain chemicals.

Levels of the neurotransmitter N-acetylaspartylglutamate (NAAG), the most plentiful peptide transmitter in the brain, stood out. At the same time patients came in for their MRI scan, they completed eight different cognitive tests. The researchers found a strong correlation between levels of NAAG in the right hippocampus and performance on six of the eight cognitive tests. The lower the levels of NAAG, the worse the subjects performed.

Dr. Kaplin noted that the availability of stronger MRI magnets in recent years made the NAAG-related findings possible. Buoyed by the strength of the correlation, Dr. Kaplin and his coworkers set about determining if the findings were more than incidental.

Dr. Kaplin then contacted Barbara S. Slusher, PhD, MAS, director of the Johns Hopkins Brain Science Institute NeuroTranslational Drug Discovery Program, who has spent years studying NAAG and its metabolism in the brain. Slusher and her colleagues had identified novel drugs that could block the breakdown of NAAG into its component parts by inhibiting the enzyme glutamate carboxypeptidase II (GCPII), including 2-PMPA. “For years, this has been a treatment in search of a disease,” Dr. Slusher stated.

Teaming up with Kristen A. Rahn, PhD, a psychiatry instructor at the Johns Hopkins University School of Medicine, the researchers bred mice with the rodent version of MS and treated them with 2-PMPA. “Before we could even consider progressing to human trials with this class of drugs, the key was to show that the finding of reduced NAAG in the brains of MS patients was causally related to, and not just correlated with, their cognitive impairment, and to do this we needed to test this out in an animal model of MS,” Dr. Rahn noted.

The scientists discovered that 2-PMPA was able to increase the NAAG levels in the MS mice close to those of a comparative set of mice without the disease. Although the mice still showed physical signs of MS, such as dragging limbs and an inability to run quickly, their learning and memory improved significantly.

To evaluate learning and memory, the mice were positioned in a maze with one escape hatch but a lot of dead ends. On day 1, all of the mice meandered bout and could not find the right escape hole. By day 4, healthy mice and mice with MS given 2-PMPA went directly to the escape hole. They were able to find the hole twice as quickly as those mice with MS but no drug.

The mice also were assessed for fear conditioning, a marker for memory. On day 1, a tone was played and then the mice were given a mild shock. Four days later, the researchers discovered that the healthy control mice and mice with MS given 2-PMPA froze in fear much longer when they heard the tone than other mice with untreated MS, signifying a stronger memory.

Dr. Kaplin reported that, historically, researchers have considered potential MS agents to be failures if they did not lessen physical symptoms in the mouse model. However, whereas 2-PMPA did not reduce physical disability, it is worth pursuing as a treatment for its extraordinary capacity for improving memory and learning.

Dr. Kaplin hopes that pharmaceutical companies will have a renewed interest in the development of drugs such as 2-PMPA for cognition improvement in MS and perhaps other neurodegenerative disorders. Because 2-PMPA is not orally active, the researchers are working on new nanotechnology-based delivery systems to get the agent to the brain. Moreover, Dr. Slusher is collaborating with the pharmaceutical company Eisai, Inc. (Woodcliff Lake, NJ, USA) to develop new drugs that could be taken orally.
“We are encouraged that there could be a way to enhance cognition in people with MS,” Dr. Kaplin concluded. “It’s something these patients desperately need.”

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